Increased Medial Temporal Tau Positron Emission Tomography Uptake in the Absence of Amyloid-β Positivity
Authors: Alejandro Costoya-Sánchez, Alexis Moscoso, Jesús Silva-Rodríguez, Michael J. Pontecorvo, Michael D. Devous, Pablo Aguiar, Michael Schöll, Michel J. Grothe, Michael W Weiner, Paul Aisen, Ronald Petersen, Clifford R Jack, William Jagust, John Q Trojanowki, Arthur W Toga, Laurel Beckett, Robert C Green, Andrew J Saykin, John C Morris, Richard J Perrin, Leslie M Shaw, Zaven Khachaturian, Maria Carrillo, William Potter, Lisa Barnes, Marie Bernard, Hector Gonzalez, Carole Ho, John K Hsiao, Jonathan Jackson, Eliezer Masliah, Donna Masterman, Ozioma Okonkwo, Laurie Ryan, Nina Silverberg, Adam Fleisher, Diana T Sacrey, Juliet Fockler, Cat Conti, Dallas Veitch, John Neuhaus, Chengshi Jin, Rachel Nosheny, Mariam Ashford, Derek Flenniken, Adrienne Kormos, Tom Montine, Michael Rafii, Rema Raman, Gustavo Jimenez, Michael Donohue, Devon Gessert, Jennifer Salazar, Caileigh Zimmerman, Yuliana Cabrera, Sarah Walter, Garrett Miller, Godfrey Coker, Taylor Clanton, Lindsey Hergesheimer, Stephanie Smith, Olusegun Adegoke, Payam Mahboubi, Shelley Moore, Jeremy Pizzola, Elizabeth Shaffer, Danielle Harvey, Arvin Forghanian-Arani, Bret Borowski, Chad Ward, Christopher Schwarz, David Jones, Jeff Gunter, Kejal Kantarci, Matthew Senjem, Prashanthi Vemuri, Robert Reid, Nick C Fox, Ian Malone, Paul Thompson, Sophia I Thomopoulos, Talia M Nir, Neda Jahanshad, Charles DeCarli, Alexander Knaack, Evan Fletcher, Duygu Tosun-Turgut, Stephanie R Chen, Mark Choe, Karen Crawford, Paul A Yuschkevich, Sandhitsu Das, Robert A Koeppe, Eric M Reiman, Kewei Chen, Chet Mathis, Susan Landau, Nigel J Cairns, Erin Householder, Erin Franklin, Haley Bernhardt, Lisa Taylor-Reinwald, Magdalena Korecka, Michal Figurski, Scott Neu, Kwangsik Nho, Shannon L Risacher, Liana G Apostolova, Li Shen, Tatiana M Foroud, Kelly Nudelman, Kelley Faber, Kristi Wilmes, Leon Thal, Keith A Johnson, Reisa A Sperling, Dorene Rentz, Rebecca E. Amariglio, Deborah Blacker, Rachel Buckley, Jasmeer P. Chhatwal, Brad Dickerson, Nancy Donovan, Michelle Farrell, Geoffroy Gagliardi, Jennifer Gatchel, Edmarie Guzman-Velez, Heidi Jacobs, Roos Jutten, Cristina Lois Gomez, Gad Marshall, Kate Oaoo, Enmanuelle Pardilla-Delgado, Juliet Price, Prokopis Prokopiou, Yakeel Quiroz, Gretchen Reynolds, Aaron Schultz, Stephanie Schultz, Jorge Sepulcre, Irina Skylar-Scott, Patrizia Vannini, Clara Vila-Castelar, Hyun-Sik Yang
Journal: JAMA Neurology (2023)

Importance An increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear. Objective To study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL + ) in the absence of Aβ pathology (A − ), and the association of this condition with the AD continuum. Design, Setting, and Participants A multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A + TMTL − ). Exposures Tau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments. Main Outcomes and Measures Cross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset). Results Among the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A − individuals and 78% of A + participants had increased tau PET signal in the entorhinal cortex (TMTL + ) compared with healthy younger (aged &amp;amp;lt;39 years) controls. Compared with A − TMTL − , A − TMTL + participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A + TMTL + showed faster and more cortically widespread tau PET increases. In contrast to participants with A + TMTL + , those with A − TMTL + did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A − TMTL + in the absence of increased Aβ accumulation. Participants with A − TMTL + had accelerated MTL atrophy, whereas those with A + TMTL + showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A − individuals was associated with cognitive decline, but at a significantly slower rate compared with A + TMTL + . Conclusions and Relevance In this study, individuals with A − TMTL + exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A − TMTL + are not on a pathologic trajectory toward AD.